Exposure to pathogenic microbial lipids, like lipopolysaccharide (LPS), triggers a complex and coordinated protective response by the immune system. Our laboratory investigates the novel postulate that triglyceride-rich lipoproteins and apolipoprotein E (apoE) have been co-opted to play an important role in host defense against bacterial infection, in addition to their well-established roles in lipid metabolism. Yet, precisely how these non-traditional elements of the immune system contribute to host immunocompetence is unclear. Published data indicate that apoE is protective against bacterial infection and injury as injection of this apolipoprotein has been shown to decrease LPS-induced morbidity and mortality in rodents. Also, apoE- deficient mice have an increased susceptibility to lethal infection when injected with live bacteria. But, unexpectedly, our laboratory has recently discovered that infusion of apoE increased rather than decreased mortality after cecal ligation and puncture, an in vivo model of polymicrobial sepsis. We believe that this apparent dichotomy highlights the existence of a novel activity for apoE in the sequestration and delivery of pathogenic microbial lipid antigens to thymus-derived lymphocytes (T cells). Specifically, we hypothesize that apoE, a key constituent of triglyceride-rich lipoproteins, regulates the host response to pathogenic bacterial lipids through its effects on natural killer T (NKT) cell activation and cytokine production. Through three specific aims, this proposal will investigate how apoE and NKT cells contribute to host defense against toxic bacterial lipids after cecal ligation and puncture in mice. In Aim 1, we will demonstrate that serum apoE concentrations correlate with morbidity and mortality in a murine model of polymicrobial sepsis. In Aim 2, we will demonstrate that apoE promotes the activation of NKT cells during sepsis. Lastly, in Aim 3, we will test the hypothesis that inhibition of apoE activity protects against the morbidity and mortality of sepsis. Results of our studies will yield considerable insight into the role of triglyceride-rich lipoproteins, apoE and T cells in the mammalian response to microbial infection. Moreover, our studies will simultaneously assign important new biological functions to plasma lipoproteins, further blur the boundary separating innate and adaptive immunity, and provide unique insights into the host response to infection that could yield innovative therapies for sepsis.